Intertriginous erosions

CASE #1: Hailey-Hailey disease Hailey-Hailey disease, also known as familial benign chronic pemphigus, was first described in 1939 by Howard and Hugh Hailey, who were brothers studying dermatology at Emory University in Atlanta. Controversy surrounded the brothers and their new...

Submit your diagnosis to see full explanation.

CASE #1: Hailey-Hailey disease

Hailey-Hailey disease, also known as familial benign chronic pemphigus, was first described in 1939 by Howard and Hugh Hailey, who were brothers studying dermatology at Emory University in Atlanta. Controversy surrounded the brothers and their new discovery because in 1933, a pair of French dermatologists named Gougerot and Allee described a disease they termed pemphigus congenital familial hereditaire. However, there was no histopathology to correlate with the cases, and after investigation, the clinical picture was thought to be more consistent with epidermolysis bullosa simplex.¹

There was also a debate as to whether Hailey-Hailey was a unique disease or a variant of Darier disease. This debate was solved after the molecular genetics of each disease was better understood. Although there are no exact data on the epidemiology, incidence estimates range from one to two per 100,000 people. Men and women are equally affected.

Hailey-Hailey is an uncommon autosomal dominant disorder in which mutations in the ATP2C1 gene on the 3q21-24 chromosome cause dysfunction of a Golgi-associated calcium ATPase pump, thus interfering with intracellular calcium signaling.^2,3 ATP2C1 produces a protein product, hSPCA1, that transports calcium and magnesium and sequesters calcium to the Golgi lumen. Mutations in this gene lead to impaired calcium sequestration, which eventually leads to acantholysis.

Normal Golgi calcium levels are needed to process proteins through the Golgi apparatus. When the calcium levels are reduced, the processing of junctional proteins, which are required for normal cell-to-cell adhesion, becomes impaired. Calcium deprivation also leads to actin reorganization within keratinocytes. This can alter the formation of the adherens junctions, which are also required for normal cell-to-cell adhesion.

The initial lesions usually appear in the second or third decades but presentation may be delayed until the fourth or fifth decade. Sites of predilection include the axillary folds, groin, lateral aspects of the neck, and perianal region. The scalp, antecubital and popliteal fossae, trunk, and inframammary regions are less commonly involved.

The initial lesion appears as a flaccid vesicle on normal or erythematous skin. These lesions tend to rupture easily and progress into macerated or crusted erosions, which spread in a peripheral fashion. Crusts and small vesicles may be seen within circinate borders upon close examination. Lesions tend to be painful and may interfere with daily activities. Malodor and pruritus can add to the social suffering.

The histologic picture of Hailey-Hailey disease is one of widespread acantholysis throughout the epidermis, giving the appearance of a dilapidated brick wall. A superficial perivascular lymphocytic infiltrate may also be appreciated.

In contrast to Darier disease, necrotic keratinocytes are uncommon. In more advanced lesions, acanthosis, parakeratosis, and focal crusts may be seen. Direct immunofluorescence is negative, helping to differentiate Hailey-Hailey disease from pemphigus vulgaris.

Given the intertriginous distribution of Hailey-Hailey disease, inverse psoriasis, intertrigo, irritant dermatitis, and candidiasis are often considered in the differential diagnosis. The presence of flaccid vesicles and erosions, along with the histologic examination, are often the key to the diagnosis. Although usually clinically distinguishable, Darier disease may have significant overlap with Hailey-Hailey disease. Palmoplantar papules, nail changes, and mucosal involvement are distinguishing features of Darier disease. Histologically, there is often more dyskeratosis and less acantholysis than Hailey-Hailey disease.

Grover’s disease may also have a similar histopathologic picture; however, the acantholysis in Grover’s disease tends be more focal and the clinical picture is unique, with lesions occurring in older men on the trunk. Langerhans cell histiocytosis, although clinically similar, may be confirmed by positive immunostaining for CD1a, S100, and Langerin. As mentioned previously, direct immunofluorescence is negative in Hailey-Hailey disease, thus helping to distinguish it from pemphigus vulgaris.

Patients should be instructed to wear lightweight clothing to prevent excessive friction and sweating, as these are common triggers. Topical corticosteroids, along with topical antimicrobials and cleansers, are an effective treatment regimen for many patients. If corticosteroid application commences early enough, healing of developing lesions can occur.

Refractory cases may be treated with intralesional corticosteroids at the lowest effective potency. Botulinum toxin A or surgical wide excision with grafting has also been reported to be successful in refractory cases. Such superficial ablative surgical techniques as dermabrasion, carbon dioxide, or erbium:YAG laser allow the epidermis to heal from uninvolved adnexal structures and may be equally effective.⁴ There is no strong evidence to support the use of systemic therapy in Hailey-Hailey disease.

Healing usually occurs without scarring; however, post-inflammatory hyperpigmentation is not uncommon. The disease course is unpredictable, and patients should be instructed to avoid excessive friction or heat. Complete remission as well as flares are common. Life expectancy is normal.

A biopsy performed on this patient confirmed a diagnosis of Hailey-Hailey disease. Direct immunofluorescence was negative. The patient was advised to wear lightweight clothing and avoid excessive heat. Improvement was noted after treatment with triamcinolone 0.1% ointment twice daily as needed and topical clindamycin 1% solution.

CASE #2: Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a clonal proliferative disease of Langerhans cells that primarily affects young children between age 1 and 3 years. The reported incidence of LCH varies widely, ranging from at least five per million in children to approximately one to two per million in adults. LCH is seen more commonly in boys, with a male-to-female ratio of 2:1. LCH is rarely seen in adults, but when present, there may be a slight female predominance. The most commonly afflicted sites in adults include the skin, lung, and bone.

In 1868, Paul Langerhans was the first to discover the epidermic dendritic cell, which is now known as a Langerhans cell. The four well-described variants of LCH include congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease), Hand-Schüller-Christian disease, Letterer-Siwe disease, and eosinophilic granuloma. The latter three were first described in the early twentieth century, and in 1953, Lichtenstein grouped the trio into a single disease entity termed histiocytosis X.⁵ In 1978, Hashimoto and Pritzker described congenital self-healing reticulohistiocytosis. After immunologic and ultrastructural studies, congenital self-healing reticulohistiocytosis and histiocytosis X were reclassified into a single disease spectrum known as LCH.

The pathogenesis of LCH remains unknown. Viral and immunologic etiologies have been considered, but there has been no evidence to implicate either as the cause.6 Such cytokines as IL-1, IL-2, IL-4 and IL-10, TNF-alpha, interferon-gamma, and GM-CSF have been found in elevated numbers within the lesions of patients with LCH. While these cytokines are not thought to be responsible for the development of the disease, they may promote disease-related symptoms and morbidity. A few cases of LCH appear to be hereditary; hence, a genetic basis now appears likely.⁷

There is significant clinical overlap between the four variants of LCH. Because of its clinical similarity to Hailey-Hailey disease, this discussion focuses mainly on the acute diffuse form of LCH, Letterer-Siwe disease. The disease usually develops prior to age 2 years, and most patients present prior to age 1 year. The eruptions consist of 1-to-2-mm erythematous to skin-colored papules, pustules, or vesicles that are most commonly seen in the flexural regions of the axilla, groin, and neck, as well as the scalp and trunk. The lesions tend to coalesce and may develop petechiae, purpura, crust, and secondary impetiginization. During the course of the disease, clonal LCH cells may infiltrate the lung, liver, lymph node, and bone.

The triad of bone lesions, exophthalmos, and diabetes insipidus characterizes Hand-Schüller-Christian disease. Most patients present between ages 2 and 6 years, and these individuals tend to have a chronic progressive course. Cutaneous lesions are present in approximately 30% of patients, and early lesions are similar to those seen in Letterer-Siwe disease. As the disease progresses, the lesions may become xanthomatous.

Eosinophilic granuloma is a localized variant of LCH that usually affects older children and has a predilection for the cranium. The classic manifestation of the disease is a single asymptomatic granulomatous lesion of the bone.

Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker disease) is a rapidly self-healing variant of LCH. These patients present with erythematous to brown papulonodules at birth or within the first few days of life. Several weeks after onset, the papules crust and involute.

Just as there is significant overlap between the clinical manifestations of the various subtypes of LCH, there is also histologic overlap. In a typical lesion, Langerhans cells, which are large cells with a reniform (kidney-shaped) nucleus, occupy the papillary dermis. There are usually interface changes with some epidermal infiltration of Langerhans cells.

Admixed with the LCH cells within the dermis are eosinophils, neutrophils, lymphocytes, mast cells, and plasma cells. Older lesions may become granulomatous, xanthomatous, or fibrous. LCH cells show positive immunostaining for CD1a, S100, and Langerin (CD207). They do not stain positive for factor XIIIa (a marker for dermal dentrocytes) or CD68, Mac387, and HAM56 (macrophage/monocyte markers).

The clinical differential diagnosis for LCH is vast and includes Hailey-Hailey disease, Darier disease, candidiasis, seborrheic dermatitis, intertrigo, scabies, and eczema. One should begin to suspect LCH if the disease is not getting better on routine treatment for more common conditions.

The distinctive histologic features of LCH, along with positive immunostaining for CD1a, S100, and Langerin, help clinch the diagnosis. Electron microscopy may also demonstrate Birbeck granules, which are racquet-shaped cytoplasmic structures that are pathognomonic for Langerhans cells.

Any individual with suspected LCH should undergo hematologic, pulmonary, hepatic, renal, and skeletal system evaluation to determine the extent of the disease. The organ involved and the extent of involvement dictate treatment. If skin treatment is desired, topical corticosteroids, topical antibacterial agents, photochemotherapy (psoralen UVA), and topical nitrogen mustard have been reported to be effective. Thalidomide (Thalomid) has been used in cases with extensive skin disease, including LCH.⁸ Multidrug chemotherapy is reserved for those with multisystem disease.

Patients with multisystem disease, especially those who are under age 2 years, have a high mortality rate, ranging from 38% to 54%.9 Patients who do not fall into this category tend to fare better.

Two biopsies taken on different occasions each revealed the diagnosis of LCH in this patient. A swab culture was positive for Staphylococcus aureus, which cleared with systemic antimicrobials. The man was referred to hematology-oncology, where the workup was completed. No other organ system was found to be involved. The skin disease is being treated with triamcinolone 0.1% ointment b.i.d. as needed with improvement. The patient continues to be monitored for progression to systemic disease. 

Kerri Robbins, MD, is a resident in the Department of Dermatology at Baylor College of Medicine in Houston.

References

1. Steffen C, Thomas D. Was Henri Gougerot the first to describe “Hailey-Hailey Disease”? Am J Dermatopathol. 2003;25:256-259.

2. Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a ­calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24:61-65.

3. Behne MJ, Tu CL, Aronchik I, et al. Human keratinocyte ATP2C1 localizes to the Golgi and controls Golgi Ca2+ stores. J Invest Dermatol. 2003;121:688-694. Available at www.nature.com/jid/journal/v121/n4/full/5601953a.html.

4. LeBlanc KG Jr, Wharton JB, Sheehan DJ. Refractory Hailey-Hailey disease successfully treated with sandpaper dermabrasion. Skinmed. 2011;9:263-264.

5. Lichtenstein L. Histiocytosis X: integration of eosinophilic granuloma of bone, Letterer-Siwe disease and Hand-Schüller-Christian disease as related manifestations of a single nosologic entity. AMA Arch Pathol. 1953;56:84-102.

6. McClain K, Jin H, Gresik V, Favara B. Langerhans cell histiocytosis: lack of a viral etiology. Am J Hematol. 1994;47:16-20.

7. Aricò M, Nichols K, Whitlock JA, et al. Familial clustering of Langerhans cell histiocytosis. Br J Haematol. 1999;107:883-888.

8. Chen M, Doherty SD, Hsu S. Innovative uses of thalidomide. Dermatol Clin. 2010;28:577-586.

9. Gadner H, Grois N, Aricò M, et al. A randomized trial of treatment for multisystem Langerhans’ cell histiocytosis. J Pediatr. 2001;138:728-734.